EP1848409A1 - Propranolol formulations - Google Patents
Propranolol formulationsInfo
- Publication number
- EP1848409A1 EP1848409A1 EP05813250A EP05813250A EP1848409A1 EP 1848409 A1 EP1848409 A1 EP 1848409A1 EP 05813250 A EP05813250 A EP 05813250A EP 05813250 A EP05813250 A EP 05813250A EP 1848409 A1 EP1848409 A1 EP 1848409A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- propranolol
- dosage form
- released
- hours
- coating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 229960003712 propranolol Drugs 0.000 title claims abstract description 47
- 239000000203 mixture Substances 0.000 title claims abstract description 22
- 238000009472 formulation Methods 0.000 title abstract description 6
- 238000013270 controlled release Methods 0.000 claims abstract description 32
- 239000011248 coating agent Substances 0.000 claims abstract description 27
- 238000000576 coating method Methods 0.000 claims abstract description 27
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 17
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- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Definitions
- Propranolol [l-(isopropyl amino)-3-(l-naphthyloxy)-2-propanol] is a beta- adrenergic blocking agent and as such is a competitive inhibitor of the effects of catecholamines at beta-adrenergic receptor sites.
- the principal effect of propranolol is to reduce cardiac activity by diminishing or preventing beta-adrenergic stimulation.
- By reducing the rate and force of contraction of the heart, and decreasing the rate of conduction of impulses through the conducting system the response of the heart to stress and exercise is reduced.
- Propranolol is also used in the treatment of cardiac arrhythmias to block adrenergic stimulation of cardiac pacemaker potentials. Propranolol is also beneficial in the long- term treatment of hypertension. Other uses of propranolol are in the treatment of migraine and anxiety.
- the present invention addresses the need for improved propranolol dosage forms, particularly controlled-release dosage forms.
- a composition comprises a core comprising a pharmaceutically acceptable propranolol salt disposed on a sugar sphere; and a coating disposed on the core, the coating comprising about 70:30 to about 85:15 of ethylcellulose:polyvinylpyrrolidone.
- a dosage form comprises a core comprising a pharmaceutically acceptable propranolol salt disposed on a sugar sphere; and a coating disposed on the core, the coating comprising polyvinylpyrrolidone and ethylcellulose; wherein the dosage form comprises one type of controlled-release coated core; and wherein the average C max of the dosage form is about 120 ng/mL to about 250 ng/mL and the average AUC 0- O 0 of the dosage form is about 3000 ng hr/mL to about 4000 ng hr/mL when measured under fasting conditions, or wherein the average C max of the dosage form is about 80 ng/mL to about 200 ng/niL and the average AUC 0-00 of the dosage form is about 1600 ng hr/mL to about 4375 ng hr/mL when measure under fed conditions.
- Also included is a method of treating a human comprising administering a pharmaceutically effective amount of the disclosed dosage form to a human in need of treatment for angina, cardiac arrhythmia, or hypertension.
- active agent is meant to include solvates (including hydrates) of the free compound or salt, crystalline and non-crystalline forms, as well as various polymorphs. Unless otherwise specified, the term “active agent” is used herein to indicate propranolol or a pharmaceutically acceptable salt thereof. For example, an active agent can include all optical isomers of propranolol and all pharmaceutically acceptable salts thereof either alone or in combination.
- “Pharmaceutically acceptable salts” includes derivatives of propranolol, wherein the propranolol is modified by making non-toxic acid or base addition salts thereof, and further refers to pharmaceutically acceptable solvates, including hydrates, of such compounds and such salts.
- pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues; and the like, and combinations comprising one or more of the foregoing salts.
- the pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the propranolol.
- non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts.
- inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
- other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like
- alkaline earth metal salts such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts.
- Organic salts includes salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH 2 ) n -COOH where n is 0-4, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, and the like; and amino acid salts such as argin,
- oral dosage form is meant to include a unit dosage form prescribed or intended for oral administration.
- An oral dosage form may or may not comprise a plurality of subunits such as, for example, microcapsules or microtablets, packaged for administration in a single dose.
- subunit is meant to include a composition, mixture, particle, etc., that can provide an oral dosage form alone or when combined with other subunits.
- part of the same subunit is meant to refer to a subunit comprising certain ingredients.
- Dissolution profile as used herein, means a plot of the cumulative amount of active ingredient released as a function of time.
- the dissolution profile can be measured utilizing the Drug Release Test ⁇ 724>, which incorporates standard test USP 26 (Test ⁇ 711>).
- a profile is characterized by the test conditions selected.
- the dissolution profile can be generated at a preselected apparatus type, shaft speed, temperature, volume, and pH of the dissolution media.
- a first dissolution profile can be measured at a pH level approximating that of the stomach.
- a second dissolution profile can be measured at a pH level approximating that of one point in the intestine or several pH levels approximating multiple points in the intestine.
- a highly acidic pH may simulate the stomach and a less acidic to basic pH may simulate the intestine.
- highly acidic pH is meant a pH of about 1 to about 4.
- less acidic to basic pH is meant a pH of greater than about 4 to about 7.5, preferably about 6 to about 7.5.
- a pH of about 1.2 can be used to simulate the pH of the stomach.
- a pH of about 6 to about 7.5, specifically about 6.8, can be used to simulate the pH of the intestine.
- Release forms may also be characterized by their pharmacokinetic parameters.
- “Pharmacokinetic parameters” are parameters which describe the in vivo characteristics of the active agent over time, including for example the in vivo dissolution characteristics and plasma concentration of the active agent.
- C max is meant the measured concentration of the active agent in the plasma at the point of maximum concentration.
- C 2 4" is meant the concentration of the active agent in the plasma at about 24 hours.
- T max refers to the time at which the concentration of the active agent in the plasma is the highest.
- AUC is the area under the curve of a graph of the concentration of the active agent (typically plasma concentration) vs. time, measured from one time to another.
- instant-release is meant a dosage form designed to ensure rapid dissolution of the active agent by modifying the normal crystal form of the active agent to obtain a more rapid dissolution.
- immediate-release it is meant a conventional or non- modified release in which greater then or equal to about 75% of the active agent is released within two hours of administration, preferably within one hour of administration.
- controlled-release it is meant a dosage form in which the release of the active agent is controlled or modified over a period of time. Controlled can mean, for example, sustained-, delayed- or pulsed-release at a particular time. Alternatively, controlled can mean that the release of the active agent is extended for longer than it would be in an immediate-release dosage form, e.g., at least over several hours.
- Dosage forms can be combination dosage forms having both immediate release and controlled release characteristics, for example, a combination of immediate release pellets and controlled release pellets.
- the immediate release portion of the dosage form may be referred to as a loading dose.
- the formulations described herein exhibit bioequivalence to the marketed drug product, for example INDERAL ® LA.
- INDERAL ® LA capsules release propranolol at a slow and predictable rate.
- Bioequivalence is defined as "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study" (21 CFR 320.1).
- bioequivalence of a dosage form may be determined according to the Federal Drug Administration's (FDA) guidelines and criteria, including "GUIDANCE FOR INDUSTRY BIOAVAILABILITY AND BIOEQUVALENCE STUDIES FOR ORALLY ADMINISTERED DRUG PRODUCTS— GENERAL CONSIDERATIONS" available from the U.S.
- FDA Federal Drug Administration's
- DHHS Department of Health and Human Services
- FDA Food and Drug Administration
- CDER Center for Drug Evaluation and Research
- GUIDANCE FOR INDUSTRY STATISTICAL APPROACHES TO ESTABLISHING BIOEQUIVALENCE
- DHHS Department of Health and Human Services
- FDA Food and Drug Administration
- CDER Center for Drug Evaluation and Research
- GUIDANCE FOR INDUSTRY STATISTICAL APPROACHES TO ESTABLISHING BIOEQUIVALENCE
- BIOEQUIVALENCE STUDIES USING A STANDARD TWO-TREATMENT CROSSOVER DESIGN
- the subjects chosen for the study should be randomly assigned to the sequences of the study.
- the variances associated with the two treatments, as well as between the sequence groups, should be equal or at least comparable.
- the main effects of the statistical model, such as 25 subject, sequence, period and treatment effect for a standard 2 x 2 crossover study, should be additive. There should be no interactions between these effects.
- the residuals of the model should be independently and normally distributed. In other words, data from bioequivalence studies should have a normal distribution.
- unit dosage forms of controlled-release propranolol hydrochloride are provided that will release the drug into an aqueous environment in a manner similar to that of INDERAL ® LA when tested under in vitro and/or in vivo conditions, hi some embodiments, the unit dosage forms may have similar behavior to INDERAL ® LA in vitro but not in vivo, and vice versa.
- the controlled-release dosage forms may be optimized to obtain release profiles similar to that of INDERAL ® LA, when both the reference product and the dosage forms described herein are tested by the United States Pharmacopoeia method for Propranolol Hydrochloride Extended Release Capsules.
- the disclosed unit dosage forms may be bioequivalent to INDERAL ® LA when compared on an mg-by-mg basis.
- the dosage forms described herein may be physically and chemically stable dosage forms (i.e., exhibiting drug release profiles and degradation profiles statistically similar to that at the initial time point) when subjected to stability studies.
- a controlled-release propranolol dosage form comprises a core comprising a propranolol-coated inert sphere, wherein the core is coated with a controlled-release coating composition comprising polyvinylpyrrolidone and ethylcellulose. It has been unexpectedly found by the inventors herein that particular controlled-release coated spheres can be employed to provide dosage forms having bioavailability comparable to INDERAL ® LA. In one embodiment, the coated spheres can be used as a single type of subunit in a dosage form. In another embodiment, the controlled-release coated spheres can be one of two or more types of subunits in a dosage form.
- the controlled-release propranolol formulation is based on pellets having an inert core component.
- suitable inert cores include for example, sugar spheres, particulate microcrystalline cellulose, silicon dioxide spheres, wax beads such as prilled waxes, and combinations comprising one or more of the foregoing inert cores.
- the core comprises non-pareil sugar seeds (sugar spheres, USP XXII) having an average size of about 25 to about 35 mesh (500 to 710 micrometers), or about 25 to about 30 mesh (600 to 710 micrometers), or about 30 to about 35 mesh (500-600 micrometers).
- a composition comprising propranolol (e.g., propranolol hydrochloride) is disposed on the inert core in an amount sufficient to provide a dosage form comprising about 20 to about 200 mg of propranolol hydrochloride (e.g., 60 mg, 80 mg, 120 mg, and 160 mg).
- propranolol e.g., propranolol hydrochloride
- the cores may be formed by coating (e.g., spraying) the sugar spheres with an aqueous or non-aqueous suspension which comprises the propranolol.
- the propranolol may be coated onto the sugar sphere in the presence of, for example, a binder, a filler, a solubilizer, and other additives, and combinations comprising one or more of the foregoing additives.
- the binder may be, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, and the like, and combinations comprising one or more of the foregoing binders.
- the binder may comprise, for example, hydroxypropylcellulose, such as hydroxypropylcellulose NF 75-150 cps.
- the suspension medium may comprise, for example, a solvent such as isopropyl alcohol, ethanol, water, and the like, and combinations comprising one or more of the foregoing solvents.
- the cores e.g., sugar spheres comprising propranolol
- a controlled-release coating composition that provides for the controlled release of propranolol.
- the controlled-release coating composition is applied (e.g., by spraying) to the cores to form a controlled-release coating disposed on the cores.
- the controlled-release coating composition comprises polyvinylpyrrolidone and ethylcellulose.
- the ratio of ethylcellulose to polyvinylpyrrolidone may be 70:30 to 85:15, or 75:25 to 80:20.
- the components of the controlled-release coating may be characterized by their viscosity measured as a 2% solution in 20:80 ethanol :toluene at 20°C.
- a suitable form of ethylcellulose is that having a viscosity of about 5 cps to about 20 cps at 20°C. More specifically, the ethylcellulose has a viscosity of about 12 cps to about 16 cps at 20 0 C.
- a suitable form of polyvinylpyrrolidone is that having a viscosity of 5.5 to 8.5 cps at 20 0 C.
- the coating may optionally comprise a plasticizer, for example a vegetable oil, such as castor oil, or glycerol; a glyceryl ester of a fatty acid, such as glyceryl triacetate or glyceryl monoricinoleate; dibutyl sebacate; triethyl citrate; acetyl triethyl citrate; tributyl citrate; acetyl tributyl citrate; diethyl phthalate; dimethyl phthalate; and combinations comprising one or more of the foregoing plasticizers.
- a plasticizer for example a vegetable oil, such as castor oil, or glycerol; a glyceryl ester of a fatty acid, such as glyceryl triacetate or glyceryl monoricinoleate; dibutyl sebacate; triethyl citrate; acetyl triethyl citrate; tributyl citrate; acety
- the coating may comprise a processing agent, such as, for example, talc, kaolin, silicon dioxide, magnesium stearate, and combinations comprising one or more of the foregoing processing aids.
- a processing agent such as, for example, talc, kaolin, silicon dioxide, magnesium stearate, and combinations comprising one or more of the foregoing processing aids.
- Suitable amounts of the plasticizer and processing aid can be readily determined by one of skill in the art.
- the controlled-release coating composition also comprises a solvent to facilitate application of the composition to the cores.
- Suitable solvents include, for example, water; and alcohols such as ethanol, denatured ethanol, and methanol; and combinations comprising one or more of the foregoing solvents. It may be desirable to add methylene chloride to the coating composition
- the controlled-release coating composition can be applied to the core using a coating technique used in the pharmaceutical industry, such as fluid bed coating. Once applied and dried, the controlled-release coating may comprise 10 wt% to about 17 wt % of the total weight of the coated cores, or about 12 wt% to about 15 wt% of the total weight of the coated cores.
- the controlled-release coating may be dried before applying an optional second coating.
- a color imparting agent may be added to the controlled-release coating composition or a rapidly dissolving seal coat containing color may be coated over the controlled release coating layer provided that the seal coat is compatible with and does not affect the dissolution of the controlled-release coating layer.
- the coated core is free from added organic acid, such as, for example, citric acid, tartaric acid, succinic acid, malic acid, ascorbic acid, and fumaric acid.
- the dosage form optionally comprises a loading dose of propranolol.
- the loading dose comprises 0 percent by weight (wt%) to about 30 wt%, more specifically 0 wt% to about 15 wt% of the total weight of the combination of the loading dose and the coated cores.
- the loading dose may be, for example, in the form of an immediate-release subunits.
- the loading dose may comprise suitable excipients as are known in the art so long as the release characteristics of the loading dose are not affected.
- the coated cores and optional loading dose may be placed in a gelatin capsule or they may be made into tablets, for example, by first adding about 25 wt% to about 40 wt% of a solid pharmaceutically acceptable tablet excipient which will form a compressible mixture with the coated cores and which may be formed into a tablet without crushing the coated cores, and optionally an effective amount of a tablet disintegrating agent and a lubricant.
- the solid pharmaceutically acceptable tablet excipient may comprise, for example, lactose, dextrose, mannitol, calcium phosphate, microcrystalline cellulose, powdered sucrose, and combinations comprising one or more of the foregoing excipients.
- the tablet disintegrant may comprise crospovidone, croscarmellose sodium, dry starch, sodium starch glycolate, and the like, and combinations comprising one or more of the foregoing disintegrants.
- Suitable lubricants include, for example, calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, and combinations comprising one or more of the foregoing lubricants.
- the dosage forms disclosed herein may exhibit an in vitro dissolution profile substantially corresponding to the pattern for INDERAL ® LA when tested according to United States Pharmacopoeia dissolution test method for Propranolol Hydrochloride Extended Release Capsules (USP Apparatus 1, Baskets @ 100 rpm, Drug Release Test 1 using 900 mL of pH 1.2 buffer for 1.5 hours followed by testing in 900 mL of pH 6.8 at 4, 8, 14, and 24 hours).
- dissolution profiles may be measured at either pH 6.8 or in 0.1 M HCl.
- the coated cores have the following in vitro release profile when dissolution is performed in a pH 6.8 medium: less than 10 wt % of the propranolol released at 1 hour;
- the coated cores have the following in vitro release profile when dissolution is performed in 0.1 M HCl: less than 10 wt % of the propranolol is released after 1 hour;
- 40 wt% to 60 wt % of the propranolol is released after 6 hours; and greater than 80 wt % of the propranolol is released after 15 hours.
- the controlled-release core described herein can be formulated into propranolol dosage forms that are bioequivalent to INDERAL ® LA.
- the disclosed controlled-release compositions have an average maximum blood plasma concentration (C max ) of 80% to 125% of that of INDERAL ® LA and an average AUC 0- O 0 of 80% to 125% of that of INDERAL ® LA.
- the average C max for INDERAL ® LA when measured in the fasting mode is about 150 ng/mL to about 200 ng/mL
- the average AUCo-Q 0 when measured in the fasting mode is about 3000 ng hr/mL to about 4000 ng hr/mL.
- the average C ma ⁇ of the dosage form when measured in the fasting mode, may be about 120 ng/mL to about 250 ng/mL and the average AUCo- ⁇ about 2400 ng hr/mL to about 5000 ng hr/mL.
- the average Cm ax for INDERAL ® LA when measured in the fed mode is about 100 ng/mL to about 160 ng/mL
- the average AUC 0- O 0 when measured in the fed mode is about 2000 ng hr/mL to about 3000 ng hr/mL.
- the average C max of the dosage form may be about 80 ng/mL to about 200 ng/mL and the average AUCo-O 0 about 1600 ng hr/mL to about 4375 ng hr/mL.
- Cores comprising propranolol hydrochloride were formed by first mixing 11,390 g of propranolol hydrochloride, 19,975 g of a granulating solution comprising 799 grams of hydroxypropyl cellulose NF (75-150 cps), and denatured alcohol to form a suspension. This suspension was sprayed onto 4,811 g of sugar spheres (500 ⁇ m to 600 ⁇ m) at a flow rate of 180 g/min to 340 g/min and a product temperature of 11 0 C to 20°C. Spraying was continued until all of the suspension was coated. The cores formed weighed about 17,000 g.
- the cores were then spray coated with a controlled release coating composition comprising 8,470 g ethylcellulose (Aqualon N14 Pharm), 2,530 g Povidone USP (Plasdone K 29/32), and 209,000 g denatured alcohol. 53 kg of cores was sprayed with 158,300 g of the coating composition. After coating was complete the coated cores were dried at a temperature of 50°C.
- a randomized, single-dose, three-way crossover pilot study design may be used to evaluate the relative bioavailability of the propranolol controlled-release capsules when dosed (1 x 160 mg) under fasting conditions.
- the following pharmacokinetic parameters may be determined from the plasma concentration data: [0043]
- the area under the plasma concentration versus time curve [AUQ O - TLQQ ] may be calculated using the linear trapezoidal rule from the zero time point to the last quantifiable concentration.
- AUC O - TLQC
- AUCTLQC AUCTLQC
- AUC(O-INF) The area under the plasma concentration versus time curve from zero to infinity [AUC(O-INF)] may be calculated by adding CtZKd n , to AUC( 0- T L Q C ) where C t is the last quantifiable concentration and K e i m is the elimination rate constant.
- the AUC (O - INF > may also be designated as AUCINF.
- the maximum observed plasma concentration [C max ] may be obtained by inspection.
- the C max may also be designated as CMAX.
- the time to maximum plasma concentration [T max ] may be obtained by inspection. If the maximum plasma concentration occurs at more than one time point, the first may be chosen as TMAX. The T max may also be designated as TMAX.
- the terminal elimination rate constant [K 0 I n ,] may be obtained from the slope of the line, fitted by linear least squares regression, through the terminal points of the log(base e) of the concentration versus time plot for these points.
- the K e i m may also be designated as KELM.
- the Ti /2 may also be designated as THALF.
- the elimination of drug from the plasma may be polyphasic for some of the subjects.
- the elimination rate constants may be estimated from the plasma data for all subjects using the plasma concentrations of the elimination phase as best as can be determined from the plasma propranolol concentration vs time plots (log scale) for the individual subjects. In some cases, the elimination phase may not be well characterized. No elimination rate constant (KELM) is reported for these cases, and also no values for AUCINF and THALF are reported.
- KELM elimination rate constant
- Statistical analyses appropriate for a three-period crossover design may be performed to assess the bioequivalence of the three products when dosed.
- the analyses may be performed using SAS® software.
- the calculations for the 90% confidence interval about the ratio of the mean test value to mean reference value and for the power of the ANOVA to detect a 20% difference from the reference mean may be performed using the LSMEAN values and standard error of estimate values as generated by the SAS software.
- the ratios of geometric means and the 90% confidence intervals of the log (base e) transformed data may be calculated for AUCTLQC, AUCINF, and CMAX.
- Novel controlled-release propranolol dosage forms comprising coated spheres have been described.
- the dosage forms may advantageously be bioequivalent to the commercially available INDERAL ® LA.
Abstract
Description
Claims
Applications Claiming Priority (2)
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US10/982,207 US20060099258A1 (en) | 2004-11-05 | 2004-11-05 | Propranolol formulations |
PCT/US2005/038558 WO2006052454A1 (en) | 2004-11-05 | 2005-10-25 | Propranolol formulations |
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EP1848409A1 true EP1848409A1 (en) | 2007-10-31 |
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EP (1) | EP1848409A1 (en) |
WO (1) | WO2006052454A1 (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT1551372T (en) | 2002-09-20 | 2018-07-23 | Alpharma Pharmaceuticals Llc | Sequestering subunit and related compositions and metohds |
US20060099259A1 (en) * | 2004-11-05 | 2006-05-11 | Grant Heinicke | Propranolol formulations |
PL2526932T3 (en) | 2006-06-19 | 2017-12-29 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
JP2010506833A (en) * | 2006-10-11 | 2010-03-04 | アルファーマ,インコーポレイテッド | Pharmaceutical composition |
US20080226715A1 (en) * | 2007-03-16 | 2008-09-18 | Albert Cha | Therapeutic compositions and methods |
US20080268047A1 (en) * | 2007-04-24 | 2008-10-30 | Xavier University Of Louisiana | Controlled Release Multiple Layer Coatings |
US8623418B2 (en) | 2007-12-17 | 2014-01-07 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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PH18946A (en) * | 1983-04-21 | 1985-11-14 | Elan Corp Plc | Controlled absorption pharmaceutical composition |
JPS6327424A (en) * | 1986-07-17 | 1988-02-05 | Shionogi & Co Ltd | Sustained release pharmaceutical and production thereof |
US6350471B1 (en) * | 2000-05-31 | 2002-02-26 | Pharma Pass Llc | Tablet comprising a delayed release coating |
US6500454B1 (en) * | 2001-10-04 | 2002-12-31 | Eurand Pharmaceuticals Ltd. | Timed, sustained release systems for propranolol |
US7022342B2 (en) * | 2002-03-28 | 2006-04-04 | Andrx Corporation, Inc. | Controlled release oral dosage form of beta-adrenergic blocking agents |
US8367111B2 (en) * | 2002-12-31 | 2013-02-05 | Aptalis Pharmatech, Inc. | Extended release dosage forms of propranolol hydrochloride |
-
2004
- 2004-11-05 US US10/982,207 patent/US20060099258A1/en not_active Abandoned
-
2005
- 2005-10-25 WO PCT/US2005/038558 patent/WO2006052454A1/en active Application Filing
- 2005-10-25 EP EP05813250A patent/EP1848409A1/en not_active Withdrawn
Non-Patent Citations (1)
Title |
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See references of WO2006052454A1 * |
Also Published As
Publication number | Publication date |
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US20060099258A1 (en) | 2006-05-11 |
WO2006052454A1 (en) | 2006-05-18 |
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